Liposomes have generated a great deal of interest as drug delivery vehicles. In particular, they are constantly being investigated for their ability to improve the delivery of chemotherapeutic agents to tumors, in efforts to increase therapeutic efficacy and decrease toxicity to normal cells. As a result, several liposomal chemotherapeutic agents are now available in the clinic. STEALTH, a liposomal system coated with polyethylene glycol, avoids uptake by the reticuloendothelial system, prolonging liposome circulation time and improving drug delivery to the tumor while generally decreasing toxicity. One FDA approved STEALTH-based drug is the pegylated liposomal doxorubicin sulfate (Doxil/Caelyx).
A group of drugs which has recently attracted considerable interest in cancer medicine is the bisphosphonates. Bisphosphonates are used primarily to increase bone density and reduce the risk of fracture in patients with osteoporosis, to slow bone turnover in patients with Paget's disease of the bone, and to treat bone metastases and normalize elevated levels of blood calcium in patients with cancer [Green J. R. Biophosphonates: preclinical review, Oncologist 8 (suppl 4) 3-13, 2004]. Zoledronic acid and other N-containing bisphosphonates have also been found to interfere with critical processes in cell signaling and growth at nanomolar concentrations and are currently under evaluation for use in combination therapies for various anti-tumor applications irrespective of bone metastases [Neville-Webbe H L, Gnant M, Coleman R E. Potential anticancer properties of bisphosphonates. Semin Oncol 37 (Suppl 1):553-65, 2010.]. In addition to direct anti-tumor effect, anti-angiogenic effects [Caraglia M, Santini D, Marra M, Vincenzi B, Tonini G, Budillon A. Emerging anti-cancer molecular mechanisms of aminobisphosphonates. Endocr Relat Cancer 13(1):7-26, 2006] and immunological effects that can mediate indirect antitumor effects have also been demonstrated [Goto S, Noguchi A, Jinguji H, Takahara M. The therapeutic potential of immuno-cell therapy of cancer in combination with aminobisphosphonates. AntiCancer Research 26: 3989-3996, 2006].
However, bisphosphonates are rapidly cleared from plasma by the kidneys and, apart from bone, have very low cellular permeability and minimal tissue penetration and this substantially limits their anti tumor efficacy.
Bisphosphonate-liposomes formulations have been described, for example, in US application publication No. 2007/0218116 which describes a method for treating or preventing tumor growth and metastasis by administrating liposomal bisphosphonates. In addition, delivery of zoledronic acid encapsulated in folate-targeted liposome which resulted in potent in vitro cytotoxic activity on tumor cells was also described [Hilary Shmeeda, Yasmine Amitay, Jenny Gorin, Dina Tzemach, Lidia Mak, Joerge Ogorka, Saran Kumar, J. Allen Zhang, Alberto Gabizon in Journal of Controlled Release 146 (2010) 76-83].
US application publication No. 2004/0161457 describes a method for administrating a therapeutic compound encapsulated in liposome to multi-drug resistant cancer cells. This method also included a covalently attached folate ligand to the liposome carrier.